Desensitization is a poorly understood phenomenon characteristic of most or all receptors. We propose an electrophysiological study of neurotransmitter desensitization using two preparations: the isolated nervous system of Aplysia, where the large size of the neuronal cell bodies makes possible a rigorous biophysical analysis of ionic and metabolic mechanisms, and the submerged and perfused rat prepyriform brain slice, in which one can study receptors in a mammalian central nervous system tissue using the techniques of population field potentials, extra- and intracellular recordings from single neurons and voltage clamping of a least those parts of the cell close to the cell body. We propose to study and compare desensitization to several different transmitters, including acetylcholine, dopamine, glutamic acid, serotonin, GABA and several peptides. Since in the Aplysia nervous system there are multiple ionic responses to the same transmitter, we will compare the kinetics and properties of desensitization for different ionic responses to acetylcholine. The overall questions to be asked include whether there are general properties of the process of desensitization which are common to all systems, whether desensitization is a result of a single process or two or more mechanisms and what are the ionic and metabolic dependencies of each of the possible mechanisms. Our preliminary results suggest that at least some Aplysia receptors show two components of desensitization, indicating at least two separate mechanisms as is the case at frog neuromuscular junction. Particular attention will be given to a determination of whether desensitization is a property of the neurotransmitter receptor or the associated channel or ionophore. This is an appropriate question to ask in Aplysia, since the various receptors and ionic responses are known. In addition investigation of the properties of desensitization to conventional neurotransmitters in the mammalian preparation we will investigate the existence of peptide receptors, study desensitization for at least one representative peptide, and investigate any modulatory effects of the various peptides on desensitization to other neurotransmitters. Finally we will attempt to demonstrate that this process has a physiologic role by study of natural synapses in both preparations.